Influence of the Basal Ganglia on Cerebellar Action

描述(由申请人提供)： 成像和微电子学的进步现在使神经外科医生能够识别大脑的小区域，并植入电极来激活这些区域的细胞。脑深部刺激(DBS)被证明是控制与基底节疾病相关的运动障碍的一种令人惊讶的有效方法，如帕金森氏病。在帕金森氏症患者中，DBS可以消除或减少震颤、动作迟缓和药物诱导的运动障碍。这些运动障碍通常在疾病的晚期完全丧失能力。最近的多组研究表明，DBS可以为帕金森患者提供持续数年的有效症状缓解。然而，DBS的使用还处于初级阶段，没有人知道合适的大脑区域来刺激以实现最佳的行为改善。 我们研究的目标是了解神经系统是如何控制肢体运动的。我们特别感兴趣的是描述大脑中控制肢体的区域，这些区域在伸手抓住物体的过程中控制肢体。帕金森氏症患者在启动和执行伸展抓取时遇到了困难，但通过刺激或破坏基底节的特定区域可以改善这种运动。我们认为，基底神经节的输出干扰了接受小脑输入的脑干运动核团的正常运作。我们的研究已经确定了猫的几个脑干区域，它们整合了基底节和小脑的输出。我们的同事将这些发现应用于指导DBS在人类中的应用，并有效地缓解了与帕金森氏症和多发性硬化症相关的运动症状。拟议的研究将以猫为对象：1)识别和表征在伸展到抓取过程中放电的基底节输出核团中的细胞。2)通过用化学物质暂时灭活或刺激这些细胞，并记录它们对运动的影响，来确定这些细胞对达到和抓住它们的重要性。3)注射6-OHDA破坏多巴胺能细胞，建立单侧帕金森病动物模型。4)试图通过灭活或激活脑干的特定区域来使6-OHDA模型的肢体运动正常化。这些数据将帮助我们了解DBS是如何工作的，并将确定DBS在运动障碍治疗中的候选区域。

DESCRIPTION (provided by applicant): Advances in imaging and micro-electronics now enable neurosurgeons to identify small regions of the brain and implant electrodes to activate cells in those regions. Deep brain stimulation (DBS) is proving to be a surprisingly effective approach for the control of movement disorders associated with diseases of the basal ganglia, such as Parkinson's disease. In Parkinson's patients, DBS can eliminate or reduce tremor, akinesia and drug-induced dyskinesias. These motor disorders are often totally disabling in advanced stages of the disease. Recent multi-group studies have demonstrated that DBS can provide effective symptomatic relief to Parkinson patients for periods extending over several years. However, the use of DBS is in its infancy, and no one knows the appropriate brain regions to stimulate to achieve optimal behavioral improvement. The goal of our research is to understand how the nervous system controls limb movements. We are particularly interested in characterizing regions of the brain that control the limb during reaching to grasp an object. Parkinson's patients experience difficulty in initiating and performing the reach-to-grasp, but the movement can be improved by stimulating or destroying specific regions of the basal ganglia. We believe that output from the basal ganglia interferes with normal operation of brainstem motor nuclei that receive input from the cerebellum. Our research has identified several brainstem regions of the cat that integrate basal ganglia and cerebellar output. Our colleagues have applied these findings to guide DBS in the human and have produced effective relief of motor symptoms related to Parkinson's disease and multiple sclerosis. The proposed studies will use cats as subjects to: 1) Identify and characterize cells in the basal ganglia output nuclei that discharge during reaching to grasp. 2) Determine the importance of these cells for reaching and grasping by temporarily inactivating or stimulating them with chemical substances and recording effects on movement. 3) Develop a unilateral model of Parkinson's disease by destroying dopaminergic cells with injections of 6-OHDA. 4) Attempt to normalize limb movements in the 6-OHDA model by inactivating or activating specific regions of the brainstem. The data will help us understand how DBS works and will identify candidate regions for the use of DBS in the treatment of motor disorders.